Benzopyran derivatives

ABSTRACT

Benzopyran derivatives represented by formula (I): ##STR1## wherein X represents =O, =S, =N-Z (Z represents a lower alkyl group, etc.), or =CHNO 2  ; Y represents a substituted amino group, an alkoxy group, an alkylthio group, etc., and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  each represent a hydrogen atom, a lower alkyl group, etc., are disclosed. The benzopyran derivatives exhibit K +   channel activating activities and are widely applicable as antiasthmatics, antiepileptics, and the like.

FIELD OF THE INVENTION

This invention relates to a novel benzopyran derivative useful as pharmaceuticals.

BACKGROUND OF THE INVENTION

Benzopyran derivatives having various pharmacological activities have hitherto been known. For example, various benzopyran derivatives in which the carbon atom at the 4-position of the benzopyran ring is directly bonded to a nitrogen atom are disclosed in Japanese Patent Application Laid-Open Nos. 60-97974, 61-47416, 63-165317, 63-196581, 63-201182, 63-303977, 64-26578, 64-38087, and 2-129184, and Journal of Medical Chemistry, Vol. 33, No. 6, pp. 1529-1541 (1990). The literatures report that these compounds possess antihypertensive activity and are useful for the treatment of heart diseases.

Of the benzopyran derivatives disclosed, Cromakalim having formula: ##STR2## has recently attracted attention as a new type of hypotensires which acts on the K⁺ channel, similar to Nicorandil and Pinacidil.

Benzopyran derivatives in which the 4-carbon atom on the benzopyran ring is not bonded directly to a nitrogen atom are disclosed in Japanese Patent Application Laid-Open Nos. 63-303977 and 64-38087, Journal of Heterocyclic Chemistry, Vol. 11, No. 5, pp. 797-802 (1974), and Journal of Medical Chemistry, Vol. 33, No. 6, pp. 1529-1541 (1990).

Further, WO 90/14346 (published on Nov. 29, 1990, after the priority date of the present invention) discloses compounds having an amido group or a thioamido group at the position of the benzopyran ring thereof.

DISCLOSURE OF THE INVENTION

The inventors have conducted extensive and intensive investigations on synthesis of benzopyran derivatives with the 4-carbon atom on the benzopyran ring thereof being not bonded directly to a nitrogen atom which are equal or superior to Cromakalim in activity on the K⁺ channel and their activities on the K⁺ channel. As a result, they have found that un-reported, novel benzopyran derivatives described below possess the above-mentioned pharmacological activities and thus completed the present invention based on this finding.

The compounds according to the present invention are represented by formula (I): ##STR3## wherein X represents an oxygen atom, a sulfur atom, =N-Z, or =CHNO₂, wherein Z represents a hydrogen atom, a lower alkyl group, an aryl group, a hydroxyl group, a lower alkoxy group, a cyano group, a carbamoyl group, or a sulfamoyl group; Y represents --NR₈ R₉, --OR₁₀, or --SR₁₁, wherein R₈ and R₉, which may be the same or different, each represent a hydrogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted unsaturated lower alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted hetero-aryl group, or they are taken together with the nitrogen atom to form a substituted or unsubstituted heterocyclic ring, and R₁₀ and R₁₁ each represent a hydrogen atom, a lower alkyl group, or an aryl group; R₁ represent a hydrogen atom, a lower alkyl group, or an aryl group, or it is directly bonded to R₂ to form a single bond; R₂ and R₃, which may be the same or different, each represent a hydrogen atom or a hydroxyl group, or they are taken together to form =O, or R₂ is directly bonded to R₁ to form a single bond; R₄ and R₅, which may be the same or different, each represent a hydrogen atom or a lower alkyl group, or they are taken together to form a polymethylene group; and R₆ and R₇, which may be the same or different, each represent a hydrogen atom, a lower alkyl group, a lower haloalkyl group, a halogen atom, a lower alkoxy group, a lower haloalkoxy group, an amido group, an acylamino group, a nitro group, a cyano group, an ester group, a lower alkylsulfonyl group, or an arylsulfonyl group, or they are taken together to form =N--O--N=.

In the definition for symbols in formula (I), the term "lower alkyl group" means an alkyl group having from 1 to 6, and preferably from 1 to 4, carbon atoms. Examples of such a lower alkyl group are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl groups.

The term "aryl group" means a monovalent substituent derived from aromatic hydrocarbons by removing one hydrogen atom therefrom. Specific examples of such an aryl group are phenyl, tolyl, xylyl, biphenyl, naphthyl, anthryl, and phenathryl group, with a phenyl group being particularly preferred. The carbon atom(s) on the ring of the aryl group may be substituted with one or more groups, e.g., a halogen atom, a lower alkyl group, an amino group, a nitro group, and a trifluoromethyl group. The term "hetero-aryl group" means an aryl group containing a hereto atom. Specific examples of such a hetero-aryl group are pyridyl, pyrimidinyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, and tetrazolyl groups. These hetero-aryl groups may have substituent(s) on the ring thereof.

The term "lower alkoxy group" means an alkoxy group having from 1 to 6, and preferably from 1 to 4, carbon atoms. Examples of such a lower alkoxy group are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, and t-butoxy groups.

The term "halogen atom" includes chlorine, bromine, fluorine, and iodine atoms, with a chlorine atom being particularly preferred.

The term "cycloalkyl group" preferably includes those having from 3 to 8 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

The term "nitrogen-containing heterocyclic ring" includes aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazyl, and morpholino groups.

Substituents which may be on these groups include a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group, a nitro group, a lower haloalkyl group, a lower haloalkoxy group, and a cyano group.

The compounds represented by formula (I) can be prepared, for example, by reacting a benzopyran compound represented by formula (II): ##STR4## wherein R₄, R₅, R₆, and R₇ are as defined above; and R₁₂ represents a hydrogen atom, a lower alkyl group, or an aryl group, with a compound represented by formula (III): ##STR5## wherein X and Y are as defined above; and L represents a releasable group, e.g., a halogen atom, --OR₁₃, and --S(O)_(n) R₁₄, wherein R₁₃ and R₁₄ each represent a hydrogen atom, a lower alkyl group, or an aryl group, and n represents O or an integer of 1 or 2, in an inert solvent in the presence of a base.

The base which can be used here includes sodium hydride, a sodium alkoxide, a potassium alkoxide, an alkyl lithium, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

The compounds of formula (I) according to the present invention can also be prepared by reacting the compound represented by formula (II) with a compound represented by formula (IV):

    X=C=W                                                      (IV)

where X is as defined above; and W represents an oxygen atom, a sulfur atom, or N-R₁₅, wherein R₁₅ represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted unsaturated lower alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted hetero-aryl group.

The compound represented by formula (IV) includes methyl isothiocyanate.

In addition, the compounds of formula (I) can be obtained by reducing a compound represented by formula (V): ##STR6## wherein X, Y, R₄, R₅, R₆, R₇, and R₁₂ are as defined above; or by dehydrating a compound represented by formula (VI): ##STR7## wherein X, Y, R₄, R₅, R₆, and R₇ are as defined above, or by reducing the 3,4-double bond of the compound obtained by the dehydration.

The reduction can be carried out by reacting with a reducing agent, such as metal borohydrides or hydrides, e.g., NaBH₄, KBH₄, LiBH₄, NaBH₃ CN, and LiAlH₄, in an inert solvent or by catalytic reduction using palladium-on-carbon, Raney nickel, etc.

The dehydration can be carried out in an inert solvent in the presence of an acid, e.g., p-toluenesulfonic acid and hydrochloric acid, or in the copresence of a base and an acid halide, e.g., p-toluenesulfonyl chloride and acetyl chloride, or an acid anhydride, e.g., acetic anhydride. Usable bases include organic bases, e.g., pyridine and triethylamine; sodium hydride, a sodium alkoxide, a potassium alkoxide, an alkyl lithium, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

More specifically, the compounds (I) of the present invention can be synthesized in accordance with the processes described in Examples hereinafter given.

Examples of the compounds (I) of the present invention include those listed in Table 1 below.

                                      TABLE 1                                      __________________________________________________________________________      ##STR8##                                                                      Compound No.                                                                   (Example No.)                                                                           R.sub.1                                                                               R.sub.2                                                                           R.sub.3                                                                            R.sub.4                                                                            R.sub.5                                                                            R.sub.6                                                                            R.sub.7                                                                            X     Y                                 __________________________________________________________________________      1        (single bond)                                                                           OH  Me  Me  H   CN  S     MeNH                               2       H      H  OH  Me  Me  H   CN  S     MeNH                               3        (single bond)                                                                           H   Me  Me  H   CN  S     MeNH                               4        (single bond)                                                                           OH  Me  Me  H   CN  S     MeS                                5        (single bond)                                                                           OH  Me  Me  H   CN  S     PhNH                               6        (single bond)                                                                           OH  Me  Me  H   CN  O     PhNH                               7        (single bond)                                                                           H   Me  Et  H   CN  S     MeNH                               8        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           S     MeNH                               9        (single bond)                                                                           H   Me  Me  H   CN  S     EtNH                              10        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           O     MeNH                              11        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           NCN   Me.sub.2 N                        12        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           NCN   MeNH                              13        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           O     CF.sub.3 CH.sub.2 NH              14        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           NCN                                                                                   ##STR9##                         15        (single bond)                                                                           H   Me  Me  H   CF.sub.3                                                                           O     MeNH                              16        (single bond)                                                                           H   Et  Me  H   CN  O     MeNH                              17        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           O     EtMeN                             18        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           O     EtO                               19        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           NCN   EtO                               20        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           NCN   NH.sub.2                          21        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           NCN                                                                                   ##STR10##                        22       H      H  H   Me  Me  H   NO.sub.2                                                                           O     MeNH                              23       H      H  H   Me  Me  H   NO.sub.2                                                                           O     Me.sub.2 N                        24       H      H  H   Me  Me  H   NO.sub.2                                                                           S     Me.sub.2 N                        25       H      H  H   Me  Me  H   NO.sub.2                                                                           NCN   Me.sub.2 N                        26        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           HON   Me.sub.2 N                        27        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           NH.sub.2 SO.sub.2 N                                                                  Me.sub.2 N                        28        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           NH.sub.2 CON                                                                         Me.sub.2 N                        29        (single bond)                                                                           OH  Me  Me  H   NO.sub. 2                                                                          O     NH.sub.2                          30        (single bond)                                                                           H   Me  Me  H   NO.sub.2                                                                           O     OH                                31        (single bond)                                                                           H   Me  Me  NON     O     NH.sub.2                          32        (single bond)                                                                           H   Me  Me  NON     O     OH                                33        (single bond)                                                                           H   Me  Me  H   AcNH                                                                               O     MeNH                              34        (single bond)                                                                           H   Me  Me  NO.sub.2                                                                           AcNH                                                                               O     MeNH                              35        (single bond)                                                                           H   Me  Me  NO.sub.2                                                                           NH.sub.2                                                                           O     MeNH                              36        (single bond)                                                                           H   (CH.sub.2).sub.3                                                                       H   NO.sub.2                                                                           NCN   Me.sub.2 N                        37        (single bond)                                                                           H   (CH.sub.2).sub.5                                                                       H   NO.sub.2                                                                           NCN   MeNH                              __________________________________________________________________________

As is apparent from Text Examples hereinafter described, the compounds (I) of the present invention exhibit excellent K⁺ channel activating activity. Hence, they are useful as an active ingredient of K⁺ channel activators, such as smooth muscle relaxants, i.e., agents for treating hyportension, asthma, angina, and urinary incontinence. The dose of the compound (I) usually ranges from about 0.0001 to 1 mg/kg/day, and preferably from 0.001 to 0.1 mg/kg/day, though varying depending on the kind and severity of the disease. The administration route is appropriately selected from oral administration, non-oral administration, topical administration, and so on according to the necessity. Carriers for the K⁺ channel activators include those commonly employed as carriers.

Among the compounds (I), those having a nitro group at the 6-position, such as compounds represented by formula (VII): ##STR11## wherein X, R₄, R₅, R₈, and R₉ are as defined above, exhibit excellent K⁺ channel activating activity (refer to Test Example). In particular, those wherein either one of R₈ and R₉ is a hydrogen atom possess great activity.

Preparation of the compounds according to the present invention will hereinafter be explained in greater detail with reference to Examples, but it should be understood that the present invention is not deemed to be limited thereto.

EXAMPLE 1 N-Methyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide

To a mixture of 1.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one, 0.6 g of methyl isothio-cyanate, and 15 ml of dried N,N-dimethylformamide was added 0.93 g of potassium t-butoxide with stirring under ice-cooling, followed by stirring for 4 hours under ice-cooling. Ice-water was added to the reaction mixture, and the mixture was made acidic with acetic acid and then extracted with diethyl ether. The ether layer was washed with water and dried over sodium sulfate. The ether layer was removed by distillation, and the residue was recrystallized from ethanol to yield 1.4 g of N-methyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.

Melting point: 186°-187° C.

NMR (CDCl₃): 1.5 (6H, s), 3.3 (3H, d), 7.0 (1H, d), 7.4 (1H, dd), 7.5 (1H, d), 7.6 (1H, br. s), 13.5 (1H, s)

MS: 274 (M⁺) ##STR12##

EXAMPLE 2 Cis-N-methyl-6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide and Trans-N-methyl-6-cyano-3,4- dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide

To a mixture of 1.4 g of N-methyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 15 ml of tetrahydrofuran, and 15 ml of methanol was added 0.23 g of sodium borohydride (NaBH₄) at -10° C. with stirring, followed by stirring at -10° C. for 2 hours and then at room temperature for 2 hours. The reaction mixture was distilled under reduced pressure, ice-water added to the residue, and the mixture made acidic with acetic acid and extracted with diethyl ether and ethyl acetate. The organic layer combined was dried over Na₂ SO₄, followed by distillation. The residue was subjected to silica gel column chromatography (developing solution: CH₂ Cl₂ :AcOEt=2:1). From the first fraction was obtained 0.1 g of cis-N-methyl-6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.

Melting point: 170°-173° C.

NMR (CDCl₃): 1.3 (3H, s), 1.5 (3H, s), 3.25 (3H, d), 4.1 (1H, d), 4.5 (1H, d), 6.9 (1H, d), 7.4 (2H), 8.4 (1H, br. s)

MS: 276 (M⁺)

From the next fraction was then recovered 0.1 g of trans-N-methyl-6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.

Melting point: 213°-214° C.

NMR (CDCl₃): 1.2 (3H, s), 1.5 (3H, s), 3.25 (3H, d), 3.5 (1H, br. s), 4.0 (1H, d), 4.25 (1H, d), 6.9 (1H, d), 7.4 (2H), 8.3 (1H, br. s)

MS: 276 (M⁺) ##STR13##

EXAMPLE 3 N-Methyl-6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide

A mixture of 0.44 g of N-methyl-6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 0.07 g of p-toluenesulfonic acid monohydrate, and 30 ml of toluene was heated at reflux for 10 hours. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH₂ Cl₂) to obtain 0.18 g of-N-methyl-6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.

Melting point: 139°-141° C.

NMR (CDCl₃): 1.5 (6H, s), 3.25 (3H, d), 5.8 (1H, s), 6.8 (1H, d), 7.4 (1H, dd), 7.7 (1H, d), 7.8 (1H, br. s)

MS: 258 (M⁺) ##STR14##

EXAMPLE 4 6-Cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-dithiocarboxylic Acid Methyl Ester

To a mixture of 2.0 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one, 2.3 g of carbon disulfide, and 20 ml of dried N,N-dimethylformamide was added 1.3 g of potassium t-butoxide while stirring and ice-cooling. After stirring for 30 minutes, a mixture of 1.56 g of methyl iodide and 8 ml of dried N,N-dimethylformamide was added thereto dropwise, followed by stirring for 1 hour under cooling with ice. Ice-water was added thereto, and the reaction mixture was extracted with diethyl ether. The ether layer was washed with water and dried over sodium sulfate. The ether layer was removed by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH₂ Cl₂) to obtain 1.2 g of 6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-dithiocarboxylic acid methyl ester as a yellow oily substance.

NMR (CDCl₃): 1.5 (6H, s), 2.7 (3H, s), 7.0 (1H, d), 7.45 (1H, dd), 8.15 (1H, d), 14.65 (1H, s)

MS: 291 (M⁺) ##STR15##

EXAMPLE 5 N-Phenyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamido

To a mixture of 0.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one, 0.37 g of phenyl isothio-cyanate, and 5 ml of dried N,N-dimethylformamide was added 0.31 g of potassium t-butoxide with under ice-cooling, followed by stirring for 5 hours under ice-cooling. Ice-water was added thereto, and the mixture was made acidic with acetic acid and extracted with diethyl ether. The extract was washed with water and dried over sodium sulfate, and the ether layer was removed by distillation. The residue was purified by silica gel column chromatography (developing solution: CH₂ Cl₂) to obtain 0.4 g of N-phenyl-6- cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.

Melting point: 300° C. or higher (softened at around 140° C. and then solidified)

NMR (CDCl₃): 1.5 (6H, s), 7.0 (1H, d), 7.25-7.65 (7H), 8.75 (1H, br. s), 13.55 (1H, br. s)

MS: 336 (M⁺) ##STR16##

EXAMPLE 6 N-Phenyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carboxamide

To a mixture of 0.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one, 0.39 g of potassium t-butoxide, and 5 ml of dried N,N-dimethylformamide was added dropwise a mixture of 0.42 g of phenyl isocyanate and 1.5 ml of dried N,N-dimethylformamide while stirring under cooling with ice. After stirring for 4 hours under ice-cooling, ice-water was added thereto, and the mixture was made acidic with acetic acid and extracted with diethyl ether. The ether layer was washed with water and dried over sodium sulfate. Diethyl ether was removed by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH₂ Cl₂) to obtain 0.17 g of N-phenyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.

Melting point: 167°-170° C.

NMR (CDCl₃): 1.5 (6H, s), 7.05 (1H, d), 7.25-7.75 (8H), 14.1 (1H, s)

MS: 320 (M⁺) ##STR17##

EXAMPLE 7 N,2-Dimethyl-6-cyano-2-ethyl-2H-1-benzopyran-4-carbothioamide

To a mixture of 0.8 g of N,2-dimethyl-6-cyano-2-ethyl-3-hydroxy-2H-1-benzopyran-4-carbothioamide and 20 ml of methanol was added 0.24 g of sodium borohydride (NaBH₄) while stirring under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was distilled under reduced pressure, and water was added to the residue. The residue was extracted with diethyl ether, and the organic layer was washed with water and dried. The solvent was removed by distillation to obtain 0.43 g of N,2-dimethyl-6-cyano-3,4-dihydro-2-ethyl-3-hydroxy-2H-1-benzopyran-4-carbothioamide. The resulting product were added 0.1 g of p-toluenesulfonic acid monohydrate and 30 ml of toluene, followed by heating at reflux for 3 hours. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH₂ Cl₂) to obtain 0.2 g of N,2-dimethyl-6-cyano-2-ethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.

Melting point: 139°-141° C.

NMR (CDCl₃): 1.0 (3H, t), 1.45 (3H, s), 1.75 (2H, m), 3.3 (3H, d), 5.8 (1H, s), 6.85 (1H, d), 7.4 (1H, dd), 7.7 (1H, d), 7.8 (1H, Br. s) ##STR18##

EXAMPLE 8 N,2,2-Trimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide

A mixture of 7.0 g of N,2,2-trimethyl-3,4-dihydro-3-hydroxy-6-nitro-2H-1-benzopyran-4-carbothioamide, 3.0 g of p-toluenesulfonic acid monohydrate, and 300 ml of toluene was heated at reflux for 1 hour. The solvent was removed from the reaction mixture by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH₂ Cl₂). Recrystallizatlon from a mixed solvent of CH₂ Cl₂, diethyl ether, and hexane gave 3.25 g of N,2,2-trimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide represented by formula shown below.

Melting point: 147°-148° C.

NMR (CDCl₃): 1.5 (6H, s), 3.3 (3H, d), 5.9 (1H, s), 6.85 (1H, d), 7.9 (1H, br. s), 8.0 (1H, dd), 8.3 (1H, d)

MS: 278 (M⁺) ##STR19##

EXAMPLE 9 N-Ethyl-6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide

A mixture of 0.14 g of N-ethyl-6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carbamide, 3.45 g of Lawesson's reagent, and 10 ml of benzene was refluxed for 1 hour. Any insoluble matter was collected by filtration with suction and washed with methylene chloride. The mother liquor and the washing were combined, and the solvent was removed therefrom by distillation. The residue was purified by silica gel column chromatography (developing solution: CH₂ Cl₂) to obtain 0.12 g of N-ethyl-6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.

Melting point: 151°-153° C.

NMR (CDCl₃): 1.33 (3H, t), 1.49 (6H, s), 3.56-4.10 (2H, m), 5.81 (1H, s), 6.85 (1H, d), 7.40 (1H, dd), 7.75 (1H, d), 7.82 (1H, br. s)

MS: 272 (M⁺) ##STR20##

EXAMPLE 10 N-Methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide

1) To a mixture of 3.2 g of 6-nitro-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one, 1.2 g of methyl isothiocyanate, and 40 ml of dried N,N-dimethylformamide was added 1.9 g of potassium t-butoxide while stirring under cooling with ice. The mixture was stirred for 3 hours under ice-cooling and then allowed to stand for 12 hours. Ice-water was added thereto, and the mixture was made acidic with hydrochloric acid and then extracted with methylene chloride. The organic layer was re-extracted with 2N NaOH. The aqueous layer was made acidic with hydrochloric acid and re-extracted with methylene chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solution: n-hexane:ethyl acetate =10:1) and recrystallized from a mixed solvent of methylene chloride and n-hexane to obtain 2.33 g of N-methyl-6-nitro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide.

Melting point: 148°-149° C.

NMR (CDCl₃): 1.5 (6H, s), 3.25 (3H, d), 6.9 (1H, d), 7.85 (1H, dd), 8.0 (1H, d), 7.4-8.2 (1H, br), 13.5 (1H, s)

MS: 294 (M⁺)

2) To a mixture of 2.08 g of N-methyl-6-nitro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide and 50 ml of methanol was added 1.33 g of sodium borohydride at -10° C. while stirring. The mixture was stirred for 24 hours while slowly raising the temperature from -10° C. up to room temperature, followed by concentration under reduced pressure. Water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of methylene chloride and n-hexane to obtain 0.6 g of N-methyl-6-nitro-3,4-dihydro-3-hydroxy-2,2-dimethyl -2H-1-benzopyran-4-carbothioamide.

Melting point: 203°-207° C.

NMR (CDCl₃ -CF₃ COOD): 1.25 (3H, s), 1.55 (3H, s), 3.3 (3H, s), 4.1 (1H, d), 4.35 (1H, d), 6.9(1H, d), 7.9 (1H, d), 8.1 (1H, dd)

MS: 296 (M⁺)

3) A mixture of 0.42 g of N-methyl-6-nitro-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 0.58 g of p-toluenesulfonyl chloride, and 30 ml of pyridine was heated under reflux for 3 hours. The reaction mixture was concentrated, and 2N hydrochloric acid was added to the residue. The mixture was extracted with dichloromethane, and the extract was dried over magnesium sulfate. The residue was purified by silica gel column chromatography (CH₂ Cl₂) and then recrystalllzed from ethyl acetate to obtain 0.25 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.

Melting point: 166°-168° C.

NMR (CDCl₃): 1.5 (6H, s), 2.95 (3H, d), 6.0 (1H, s), 6.8 (1H, d), 8.0 (1H, dd), 8.45 (1H, d), 5.6-6.4 (1H, m)

MS: 262 (M⁺) ##STR21##

EXAMPLE 11

N² -Cyano-N¹,N¹ -dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine

To a mixture of 5.25 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide obtained in the same manner as in Example 10-(3), 14.2 g of methyl iodide, and 50 ml of tetrahydrofuran was added 0.88 g of sodium hydride with stirring, followed by heating under reflux for 3 hours. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. To the residue were added 4.26 g of Lawesson's reagent and 20 ml of toluene, and the mixture was heated at reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (developing solution: methylene chloride) and then recrystallized from a mixed solvent of ethyl acetate and n-hexane to yield 4.86 g of N,N-dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide.

Melting point: 139°-141° C.

NMR (CDCl₃): 1.5 (6H, s), 3.2 (3H, s), 3.6 (3H, s), 5.65 (1H, s), 6.85 (1H, d), 7.85 (1H, d), 8.05 (1H, dd)

2) To a mixture of 2.93 g of N,N-dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 4.11 g of methyl iodide, and 30 ml of tetrahydrofuran was heated at reflux for 1 hour. When the inner temperature dropped to room temperature, 1.34 g of cyanamide and 0.44 g of sodium hydride were added thereto, followed by heating under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure. Methylene chloride was added to the residue, and any insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solution: mixture of n-hexane and ethyl acetate) and then recrystallized from a mixed solvent of ethyl acetate and n-hexane to obtain 2.57 g of N² -cyano-N¹,N¹ -dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine.

Melting point: 209°-211° C.

NMR (CDCl₃): 1.6 (6H, s), 3.0 (3H, s), 3.25 (3H, s), 5.95 (1H, s), 6.95 (1H, d), 7.7 (1H, d), 8.1 (1H, dd)

MS: 300 (M⁺) IR (KBr): 2172 cm⁻¹ (C═N) ##STR22##

EXAMPLE 12 N-Cyano-N'-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine

1) A mixture of 5.26 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide prepared in accordance with Example 10-(3), 4.26 g of Lawesson's reagent, and 20 ml of benzene was heated at reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromato- graphy (developing solution: methylene chloride) and then recrystallized from a mixture of ethyl acetate and n-hexane to obtain 4.84 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide.

Melting point: 147°-148° C.

2) A mixture of 0.56 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 0.39 g of p-toluenesulfonyl chloride, 0.21 g of triethylamine, and 3 ml of acetonitrile was heated at reflux for 30 minutes. The solvent was removed by distillation, and to the residue were added 0.27 g of cyanamide, 0.17 g of sodium hydride, and 4 ml of ethanol, followed by heating under reflux for 30 minutes. Concentrated hydrochloric acid and water were added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed successively with a 2N potassium carbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was removed by distillation, and the residue was subjected to silica gel column chromatography (developing solution: n-hexane:ethyl acetate=1:1) and then recrystallized from a mixture of ethyl acetate and diethyl ether to obtain 50 mg of the titled compound.

Melting point: 240°-243° C.

NMR (CDCl₃): 1.6 (6H, s), 3.1 (3H, d), 5.9-6.2 (1H, bs), 6.1 (1H, s), 6.9 (1H, d), 7.85 (1H, d), 8.1 (1H, dd)

MS: 286 (M⁺) IR (KBr): 2180 cm⁻¹ (C═N) ##STR23##

EXAMPLE 13 N-(2',2',2'-Trifluoroethyl)-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide

A mixture of 1.00 g of 6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxylic acid, 0.44 g of 2,2,2-trifluoroethylamine, 0.97 g of 2,2'-dipyridyl disulfide, 1.16 g of triphenylphosphine, and 20 ml of dichloromethane was stirred at room temperature for 3 hours. The solvent was removed therefrom by distillation, and the residue was purified by silica gel column chromatography (developing solution; AcOEt:n-hexane=1:1) and then recrystallized from a mixture of n-hexane and ethyl acetate to obtain 0.98 g of N (2',2',2'-trifluoroethyl)-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.

Melting point: 178°-180° C.

NMR (CDCl₃): 1.5 (6H, s) , 3.7-4.4 (2H, m), 6.1 (1H, s), 6.85 (1H, d) , 8.05 (1H, dd), 8.4 (1H, d)

MS: 330 (M⁺) ##STR24##

EXAMPLE 14 N-(N'-Cyano-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-yliminoyl)-pyrrolidin-3-ol

A mixture of 0.11 g of N-(N'-cyano-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-yliminoyl)-3-t-butyldimethyl-silyloxypyrrolidine, 0.5 ml of a 1 mol/l solution of tetra-n-butylammonium fluoride in tetrahydrofuran, and 5 ml of tetrahydrofuran was stirred for 1 hour under cooling with ice. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (AcOEt:n-hexane=1:5) and recrystallization from a mixture of n-hexane and ethyl acetate to obtain 28 mg of N-(N'-cyano-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-yliminoyl)-pyrrolidin-3-ol represented by formula shown below.

Melting point: 199°-200 ° C.

NMR (CDCl₃): 1.6 (6H, s), 1.7-4.8 (8H, m), 6.0 (1H, s), 6.9 (1H, d), 7.55-7.8 (1H, m) 8.05 (1H, dd)

MS: 342 (M⁺) ##STR25##

EXAMPLE 15 N-Methyl-6-trifluoromethyl-2,2-dimethyl-2H-1-benzopyran-4-carboxamide

A mixture of 0.17 g of N-methyl-3,4-dihydro-3-hydroxy-6-trifluoromethyl-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 0.21 g of p-toluenesulfonyl chloride, and 10 ml of pyridine was heated at reflux for 4 hours. To the reaction mixture was added 2N hydrochloric acid, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate. The residue was purified by silica gel column chromatography (CH₂ Cl₂ :methanol=100:1) and then recrystallized from a mixture of diethyl ether and n-hexane to obtain 44 mg of N-methyl-6-trifluoromethyl-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.

Melting point: 146°-150° C.

NMR (CDCl₃): 1.4 (6H, s), 2.85 (3H, d), 5.95 (1H, s), 6.1-6.7 (1H, m), 6.8 (1H, d), 6.35 (1H, dd), 7.75 (1H, d)

MS: 285 (M⁺) ##STR26##

EXAMPLE 16 N-Methyl-6-cyano-2-ethyl-2-methyl-2H-1-benzopyran-4-carbamide

A mixture of 70 mg of N-methyl-6-cyano-2-ethyl-2-methyl-2H-1-benzopyran-4-carbothioamide, 55 mg of p-toluenesulfonyl chloride, and 5 ml of pyridine was heated at reflux for 6 hours. To the reaction mixture was added 2N hydrochloric acid, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate, and purified by silica gel column chromatography (AcOEt:n-hexane=1:1) and recrystallized from a mixture of ethyl acetate and n-hexane to obtain 41 mg of N-methyl-6-cyano-2-ethyl-2-methyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.

Melting point: 152°-154° C.

NMR (CDCl₃): 0.95 (3H , t), 1.4 (3H, s), 1.8 (2H, q), 2.9 (3H, d), 6.0 (1H, s), 6.2-6.7 (1H, m), 6.8 (1H, d), 7.4 (1H, dd), 7.85 (1H, d)

MS: 256 (M⁺) ##STR27##

EXAMPLE 17 N-Ethyl-N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide

A mixture of 0.53 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide, 1.60 g of ethyl iodide, 0.09 g of sodlum hydride, and 10 ml of tetrahydrofuran was heated at reflux for 30 minutes. Dichloromethane was added to the reaction mixture, and any insoluble matter was removed by filtration. The filtrate was recrystallized from a mixture of diethyl ether and n-hexane to obtain 0.45 g of N-ethyl-N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.

Melting point: 121°-124° C.

NMR (CDCl₃): 0.9-1.5 (3H, m), 1.5 (6H, s), 2.8-3.8 (5H, m), 5.7 (1H, s), 6.95 (1H, d), 7.9 (1H, d), 8.1 (1H, dd)

MS: 290 (M⁺) ##STR28##

EXAMPLE 18 TO 20 N-Cyano-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboximidic Acid Ethyl Ester, N-Cyano-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine, and 6-Nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxylic Acid Ethyl Ester

To a mixture of 1.04 g of 4-cyano-6-nitro-2,2-dimethyl-2H-1-benzopyran and 20 ml of ethyl alcohol was added hydrogen chloride with stirring and cooling with ice. After being saturated with hydrogen chloride, the mixture was further stirred at 5° C. for 6 days. The reaction mixture was concentrated, and to the residue was added a 1:1 mixture of diethyl ether and ethyl alcohol. After trituration, the crystal was collected by filtration, washed with a mixture of ethyl alcohol and diethyl ether, and dried to obtain 1.13 g of 6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboximidic acid ethyl ester hydrochloride. A mixture of 0.94 g of the resulting compound, 0.31 g of triethylamine, 0.13 g of cyanamide, and 7 ml of ethyl alcohol was stirred at room temperature for 6 hours, followed by concentration. Water was added to the residue, and the mixture was extracted with dichloromethane. The extract was washed with 2N hydrochloric acid, dried over magnesium sulfate, and subjected to silica gel column chromatography (AcOEt:n-hexane=1:1) to isolate three components having different polarity. The component of the lowest polarity was recrystallized from a mixture of diethyl ether and n-hexane to obtain 0.15 g of 6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxylic acid ethyl ester represented by formula shown below.

Melting point: 96°-97° C.

NMR (CDCl₃): 1.4 (3H, t), 1.5 (6H, s), 4.35 (2H, q), 6.8 (1H, s), 6.85 (1H, d), 8.05 (1H, dd), 9.0 (1H, d)

MS: 277 (M⁺) ##STR29## The component of the second lowest polarity was recrystallized from a mixture of ethyl acetate and n-hexane to obtain 0.14 g of N-cyano-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboximidic acid ethyl ester represented by formula shown below.

Melting point: 91°-93° C.

NMR (CDCl₃): 1.5 (3H, t), 1.6 (6H, s), 4.6 (2H, q), 6.5 (1H, s), 6.85-7.1 (1H, m), 8.0-8.3 (2H, m)

MS: 301 (M⁺) ##STR30## The component of the highest polarity was recrystallized from a mixture of ethyl acetate and n-hexane to obtain 0.08 g of N-cyano-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine represented by formula shown below.

Melting point: 205°-207° C.

NMR (CDCl₃): 1.5 (6H, s), 5.6-6.5 (2H, m), 6.2 (1H, s), 6.9 (1H, d), 8.05 (1H, dd), 8.55 (1H, d)

MS: 272 (M⁺) ##STR31##

EXAMPLE 21 N-Cyano-N'-cyclopropyl -6-nitro-2,2-dimethyl-2H-1-benzopyran -4-carboxamidine

A mixture of 98 mg of N-cyano -6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboximidic acid ethyl ester, 30 mg of cyclopropylamine, and 1 ml of dichloromethane was stirred at room temperature for 1.5 hours. The reaction mixture was subjected to silica gel column chromatography (AcOEt:n-hexane=l:l) and then recrystallization from a mixture of acetone and n-hexane to obtain 30 mg of N-cyano-N'-cyclopropyl-6-nitro-2,2-dimethyl-2H-1-benzopyran -4-carboxamidine represented by formula shown below.

Melting point: 206°-207° C.

NMR (CDCl₃): 0.5-1.0 (4H, m), 1.5 (6H, s), 2.7-3.2 (1H, m), 5.9 (1H, s), 6.8 (1H, d), 6.9-7.4 (1H, m), 7.7 (1H, d), 8.0 (1H, dd)

MS: 312 (M⁺) ##STR32##

EXAMPLE 22 N-Methyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide

A mixture of 0.53 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide, 0.38 g of sodium borohydride, 5 ml of tetrahydrofuran, and 5 ml of methyl alcohol was stirred at room temperature for 20 minutes. 2N Hydrochloric acid was added thereto, followed by extracting with dichloromethane. The extract was dried over magnesium sulfate and recrystallized from ethyl acetate and n-hexane to obtain 0.42 g of N-methyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.

Melting point: 161°-162° C.

NMR (CDCl₃): 1.3 (3H, s), 1.4 (3H, s), 1.9-2.4 (2H, m), 2.85 (3H, d), 3.7 (1H, dd), 5.7-6.3 (1H, m), 6.85 (1H, d), 7.85-8.2 (2H, m)

MS: 264 (M⁺) ##STR33##

EXAMPLE 23 N,N-Dimethyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide

A mixture of 2.63 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide, 1.90 g of sodium borohydride, 25 ml of tetrahydrofuran, and 25 ml of methyl alcohol was stirred at room temperature for 20 minutes. 2N Hydrochloric acid was added thereto, followed by extracting with dichloromethane. The extract was dried over magnesium sulfate. The solvent was removed by distillation, and to the residue were added 7.1 g of methyl iodide, 0.44 g of sodium hydride, and 50 ml of tetrahydrofuran, followed by heating under reflux for 30 minutes. 2N Hydrochloric acid was added thereto, and the mixture was extracted with dichloromethane. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The residue was purified by silica gel column chromatography (CH₂ Cl₂) and recrystallized from a mixture of ethyl acetate and n-hexane to obtain 0.49 g of N,N-methyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.

Melting point: 162°-164° C.

NMR (CDCl₃): 1.35 (3H, s), 1.5 (3H, s), 1.75-2.5 (2H, m), 2.1 (3H, s), 2.25 (3H, s), 4.2 (1H, dd), 6.85 (1H, d), 7.8-8.2 (2H, m)

MS: 278 (M⁺) ##STR34##

EXAMPLE 24 N,N-Dimethyl-3,4-dihydro-6-nitro-2,2 dimethyl-2H-1-benzopyran-4-carbothioamide

A mixture of 0.43 g of N,N-dimethyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide, 0.33 g of Lawesson's reagent, and 2 ml of benzene was heated under reflux for 30 minutes. The reaction product was purified by silica gel column chromatography (CH₂ Cl₂) and recrystallized from a mixture of ethyl acetate and n-hexane to obtain 0.33 g of N,N-dimethyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.

Melting point: 158°-160° C.

NMR (CDCl₃): 1.3 (3H, s), 1.5 (3H, s), 1.8-2.7 (2H, m), 3.3 (3H, s), 3.6 (3H, s), 4.6 (1H, dd) 6.8 (1H, d), 7.75-8.2 (2H, m)

MS: 294 (M⁺) ##STR35##

EXAMPLE 25 N-Cyano-N',N'-dimethyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine

A mixture of 0.27 g of N,N-dimethyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 0.66 g of methyl iodide, and 2 ml of tetrahydrofuran was heated under reflux for 1 hour. To the reaction mixture were added 40 mg of sodium hydride and 44 mg of cyanamide, and refluxing was further continued for an additional period of 2 hours. Dichloromethane was added to the reaction mixture, and any insoluble matter was removed by filtration. The filtrate was purified by silica gel column chromatography (AcOEt:n-hexane=1:1) and then recrystallized from a mixture of ethyl acetate and n-hexane to obtain 90 mg of N-cyano-N',N'-dimethyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine represented by formula shown below.

Melting point: 222°-224° C.

NMR (CDCl₃): 1.35 (3H, s), 1.6 (3H, s), 1.8-5.5 (9H, m), 6.95 (1H, d), 7.8-8.3 (2H, m)

MS: 302 (M⁺) ##STR36##

EXAMPLE 26 N-Hydroxy-N',N'-dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine

A mixture of 0.30 g of N,N-dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 2.5 g of methyl iodide, and 10 ml of tetrahydrofuran was heated at reflux for 30 minutes. To the reaction mixture were added 0.37 g of hydroxylamine hydrochloride and 0.15 g of trimethylamine, and refluxing was further continued for 1.5 hours. A potassium carbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate, and purified by silica gel column chromatography (AcOEt:n-hexane=1:1) and then recrystallized from a mixture of dichloromethane and n-hexane to obtain 72 mg of N-hydroxy-N',N'-dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine represented by formula shown below.

NMR (CDCl₃): 1.55 (6H, s), 2.75 (6H, s), 5.8 (1H, s), 6.9 (1H, d), 7.4-8.2 (3H, m)

MS: 291 (M⁺) ##STR37##

EXAMPLE 27 N-Sulfamoyl-N',N'-dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine

A mixture of 0.29 g of N,N-dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 0.71 g of methyl iodide, and 2 ml of tetrahydrofuran was heated at reflux for 30 minutes. To the reaction mixture were added 105 mg of sulfamide and 44 mg of sodium hydride, followed by refluxing for 5 hours. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, purified by silica gel column chromatography (AcOEt:n-hexane=1:1), and then recrystallized from a mixture of ethyl acetate and n-hexane to obtain 0.17 g of N-sulfamoyl-N',N'-dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine represented by formula shown below.

Melting point: 212°-214° C.

NMR (CDCl₃): 1.55 (3H, s), 1.6 (3H, s), 2.9 (3H, s), 3.2 (3H, s), 4.4-4.8 (2H, m), 5.95 (1H, s), 6.9 (1H, d), 7.7 (1H, d), 8.1 (1H, dd)

MS: 354 (M⁺) ##STR38##

EXAMPLE 28 N-Carbamoyl-N',N'-dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine

To a mixture of 300 mg of N-cyano-N',N'-dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine, 10 ml of ethyl alcohol, and 10 ml of chloroform was added hydrogen chloride gas under cooling with ice. After being saturated with hydrogen chloride, the mixture was stirred at 6° C. for 10 days, followed by concentration. To the residue was added a saturated sodium hydrogencarbonate aqueous solution, and the mixture was extracted with dichloromethane. The extract was dried over sodium sulfate and purified by silica gel column chromatography (AcOEt:n-hexane=1:1) and then by recrystallization from a mixture of ethyl acetate and n-hexane to obtain 236 mg of N-carbamoyl-N',N'-dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine represented by formula shown below.

Melting point: 157°-159° C.

NMR (CDCl₃): 1.5 (3H, s), 1.55 (3H, s), 2.9 (3H, s), 3.15 (3H, s), 4.6-5.4 (2H, m), 5.7 (1H, s), 6.85 (1H, d), 7.8 (1H, d), 8.05 (1H, dd)

MS: 318 (M⁺) ##STR39##

EXAMPLE 29 3-Hydroxy-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamide

To a mixture of 41.5 g of 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran-3-one and 500 ml of dried N,N-dimethylformamide was slowly added 8.2 g of sodium hydride (60%) in a nitrogen stream while stirring under cooling with ice. After stirring for 50 minutes, 33.5 g of carbonyl diimidazole was added thereto and the mixture stirred for 1 hour. To the reaction mixture were added 11.2 g of ammonium chloride and 29 ml of triethylamine, followed by stirring at 5° C. for 12 hours and then at room temperature for 14 hours. Ice-water was added to the reaction mixture, and the mixture was washed with diethyl ether. The aqueous layer was made acidic with hydrochloric acid and extracted with a mixed solvent of ethyl acetate and diethyl ether. The organic layer was washed with water and dried. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH₂ Cl₂ :MeOH=99:1) to obtain 23.2 g of 3-hydroxy-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamide represented by formula shown below.

Melting point: 189°-191° C.

NMR (CDCl₃ -CD₃ OD): 1.50 (6H, s), 7.00 (1H, d), 7.97 (1H, dd), 8.27 (1H, d)

MS: 264 (M⁺) ##STR40##

EXAMPLE 30 2,2-Dimethyl-6-nitro-2H-1-benzopyran-4-carboxylic Acid

To a mixture of 23.2 g of 3-hydroxy-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamide, 16.6 g of sodium cyanoborohydride, and 200 ml of tetrahydrofuran was added 100 ml of acetic acid with stirring and ice-cooling, followed by stirring for 3 hours under ice-cooling and then at room temperature for 18 hours. To the reaction mixture were further added 5.6 g of sodium cyanoborohydride and 50 ml of methanol, followed by stirring at room temperature for 40 hours. The reaction mixture was distilled under reduced pressure, water was added to the residue, and the mixture was extracted with a mixed solvent of ethyl acetate and diethyl ether. The organic layer was washed with water and dried, and the solvent was removed by distillation to recover 24 g of 3,4-dihydro-3-hydroxy-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamide. To the resulting compound were added 51.5 g of p-toluenesulfonyl chloride and 400 ml of pyridine, followed by refluxing for 3 hours. The solvent was removed from the reaction mixture by distillation. Ice-water was added to the residue, and the mixture was made acidic with hydrochloric acid. The thus precipitated crystal was collected by filtration, washed with water, and dried. The crystal was further purified by silica gel column chromatography (developing solution: CH₂ Cl₂ :hexane=7:3) to give 17.9 g of 4-cyano-2,2-dimethyl-6-nitro-2H-1-benzopyran represented by formula shown below.

Melting point: 162°-164° C.

NMR (CDCl₃): 1.58 (6H, s), 6.51 (1H, s), 6.94 (1H, d), 8.15 (1H, dd), 8.23 (1H, d)

MS: 230 (M⁺) ##STR41## A mixture of 13.0 g of 4-cyano-2,2-dimethyl-6-nitro-2H-1-benzopyran, 400 ml of acetic acid, 200 ml of water, and 100 ml of concentrated sulfuric acid was heated at reflux for 1.5 hours. After adding 100 ml of concentrated sulfuric acid, the refluxing was further continued for an additional period of 1 hour. The reaction mixture was poured into ice-water. The thus precipitated crystal was washed with water, dried, and recrystallized from a mixed solvent of acetonitrile and water to obtain 11.9 g of 2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxylic acid represented by formula shown below.

Melting point: 203°-204° C. NMR (CDCl₃ -CD₃ OD)): 1.50 (6H, s), 6.80 (1H, s), 6.85 (1H, d), 8.03 (1H, dd), 8.99 (1H, d)

MS: 249 (M⁺) ##STR42##

EXAMPLE 31 6,6-Dimethyl-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole-8-carboxamide

To a mixture of 3.9 g of 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole and 80 ml of toluene was added dropwise 90 ml of a 1.0M solution of diethyl-aluminum cyanide in toluene with stirring under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into ice-water, and 2N NaOH was added thereto. The mixture was extracted with methylene chloride, and the organic layer was washed with water and dried. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH₂ Cl₂) to obtain 2.9 g of 8-cyano-6,6-dimethyl-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole represented by formula shown below.

Melting point: 136°-138° C.

NMR (CDCl₃): 1.55 (6H, s), 6.83 (1H, s), 7.03 (1H, s), 7.83 (1H, s)

MS: 227 (M⁺) ##STR43## A mixture of 0.66 g of 8-cyano-6,6-dimethyl-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole and 15 ml of concentrated sulfuric acid was stirred at room temperature for 45 hours. The reaction mixture was poured into ice-water and extracted with diethyl ether. The organic layer was washed with water, dried, and distilled to remove the solvent. The residue was purified by silica gel column chromatography (developing solution: CH₂ Cl₂ :MeOH=99:1) and recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 0.35 g of 6,6-dimethyl-6H-pyrano[2,3f]benzo-2,1,3-oxadiazole-8-carboxamide represented by formula shown below.

Melting point: 168°-169° C.

NMR (CDCl₃): 1.52 (6H, s), 6.30 (2H, br. s). 6.60 (1H, s), 7.07 (1H, s), 8.18 (1H, s)

MS: 245 (M⁺) ##STR44##

EXAMPLE 32 6,6-Dimethyl-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole-8-carboxylic Acid

In the same manner as in Example 30, except for using 1.74 g of 8-cyano-6,6-dimethyl-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole, 1.76 g of 6,6-dimethyl-6H-pyrano[2,3f]benzo-2,1,3-oxadiazole-8-carboxylic acid represented by formula shown below was obtained.

Melting point: 246°-248° C.

NMR (CDCl₃): 1.52 (6H, s), 7.07 (1H, s), 7.27 (1H, s), 8.61 (1H, s)

MS: 246 (M⁺) ##STR45##

EXAMPLE 33 N,2,2-Trimethyl-6-acetylamide-2H-1-benzopyran-4-carboxamide

A mixture of 1.55 g of N,2,2-trimethyl-6-nitro-2H-1-benzopyran-4-carboxamide, 3.84 g of stannous chloride, and 30 ml of dried ethanol was heated at reflux for 4 hours. The solvent was removed by distillation, and 15 ml of acetic anhydride was added to the residue, followed by stirring at room temperature for 17 hours. The reaction mixture was distilled under reduced pressure and 2N hydrochloric acid was added to the residue. The mixture was extracted with a mixed solvent of ethyl acetale and diethyl ether, and the organic layer was washed with water and dried. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH₂ Cl₂ :MeOH=99:1) to obtain 1.30 g of N,2,2-trimethyl-6-acetylamide-2H-1-benzopyran-4-carboxamide represented by formula shown below.

Melting point: 203°-210° C.

NMR (CDCl₃ -DMSO-d₆): 1.42 (6H, s), 2.06 (3H, s), 2.85 (3H, d), 5.99 (1H, s), 6.74 (1H. br. d), 7.50 (1H, br. s), 7.52 (1H, s), 7.60 (1H, br. d), 9.43 (1H, br. s)

MS: 274 (M⁺) ##STR46##

EXAMPLE 34 N,2,2-Trimethyl-6-acetylamide-7-nitro-2H-1-benzopyran-4-carboxamide

To a mixture of 1.16 g of N,2,2-trimethyl-6-acetylamide-2H-1-benzopyran-4-carboxamide and 15 ml of acetic acid was added a solution of 0.50 ml of fuming nitric acid in 2 ml of acetic acid while stirring under ice-cooling, followed by stirring at room temperature for 1 hours. Ice-water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate and diethyl ether. The organic layer was washed with water, dried, and distilled to remove the solvent. The residue was purified by silica gel column chromatography (developing solution: CH₂ Cl₂ :MeOH=99:1) to obtain 0.55 g of N,2,2-trimethyl-6-acetylamide-7-nitro-2H-1-benzopyran-4-carboxamide having formula shown below.

Melting point: 213°-215° C.

NMR (CDCl₃): 1.45 (6H, s), 2.23 (3H, s), 2.96 (3H, d), 6.25 (1H, br. s), 6.29 (1H, s), 7.59 (1H, s), 8.66 (1H, s), 9.92 (1H, br. s)

MS: 319 (M⁺) ##STR47##

EXAMPLE 35 N,2,2-Trimethyl-6-amino-7-nitro-2H-1-benzopyran-4-carboxamide

A mixture of 0.50 g of N,2,2-trimethyl-6-acetylamide-7-nitro-2H-1-benzopyran-4-carboxamide, 15 ml of ethanol, and 2N sodium hydroxide was stirred at room temperature for 3 hours. A saturated sodium chloride aqueous solution was added to the reaction mixture, followed by extracting with diethyl ether. The organic layer was washed with a saturated sodium chloride aqueous solution, dried, and distilled to remove the solvent to obtain 0.40 g of N,2,2trimethyl-6-amino-7-nitro-2H-1-benzopyran-4-represented by formula shown below.

Melting point: 202°-205 ° C.

NMR (CDCl₃): 1.43 (6H, s), 2.93 (3H, d), 5.91 (3H, br. s), 6.20 (1H, s), 7.13 (1H, s), 7.52 (1H, s)

MS: 277 (M⁺) ##STR48##

EXAMPLE 36 N-Cyano-N,N'-dimethyl-6-nitrospiro-[2H-1-benzopyran-2,1'-cyclobutane]-4-carboxamidine

To a mixture of 0.08 g of N,N'-dimethyl-6-nitrospiro-[2H-1-benzopyran-2,1'-cyclobutane]-4-carbothioamide, 0.42 g of iodomethane, 0.08 g of cyanamide, and 4 ml of dried tetrahydrofuran was added 0.08 g of sodium hydride (60%) while stirring under ice-cooling. The mixture was stirred at room temperature for 12 hours and then at 40° C. for 30 minutes. Ice-water was added thereto, and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (developing solution: CH₂ Cl₂ :MeOH=99:1) and recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 0.06 g of N-cyano-N,N'-dimethyl-6-nitrospiro-[2H-1-benzopyran-2,1'-cyclobutane]-4-carboxamidine represented by formula shown below.

Melting point: 185°-187° C.

NMR (CDCl₃): 1.56-2.88 (6H, m), 3.00 (3H, s), 3.24 (3H, s), 6.25 (1H, s), 6.88 (1H, d), 7.56 (1H, d), 8.01 (1H, dd)

MS: 312 (M⁺) ##STR49##

EXAMPLE 37 N-Cyano-N'-methyl-6-nitrospiro-[2H-1-benzopyran-2,1'-cyclohexane]-4-carboxamidine

To a mixture of 120 mg of N-methyl-6-nitro-spiro[2H-1benzopyran-2,1'-cyclohexane]-4-carbothioamide, 150 μl of iodoethane, and 3 ml of dried tetrahydrofuran was added 23 mg of sodium hydride (60%) with stirring and cooling with ice followed by refluxlng for 2 hours. After cooling to room temperature, 80 mg of cyanamide and 17 mg of sodium hydride (60%) were added thereto, followed by refluxing for 4 hours. Ice-water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (developing solution: ethyl acetate:hexane=2:3) recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 90 mg of N-cyano-N'-methyl-6-nitrospiro[2H-1-benzopyran-2,1'-cyclohexane]-4-carboxamidine having formula shown below.

Melting point: 244°-245° C.

NMR (CDCl₃ -CD₃ OD): 1.40-2.20 (10H, m), 2.95 (3H, d), 5.95 (1H, s), 6.85 (1H, d), 7.75 (1H, d), 8.00 (1H, dd)

MS: 326 (M⁺) ##STR50##

EXAMPLES 38 TO 315

Compounds shown in Table 2 below were synthesized in accordance with the procedures described in the foregoing Examples.

    TABLE 2       ##STR51##       (I)  Com-          Melting  IR Process pound          Point MS (KBr) of      No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 R.sub.6 R.sub.7 X Y (°      C.) (M.sup.+) (cm.sup.-1) Synthesis         38  (single bond) OH Me Me Cl Cl S MeNH 146-148 317  Example 1  39      (single bond) OH Me Me Cl Cl O PhNH 169-171 363  Example 1  40  (single      bond) OH Me Me Cl CN S MeNH 212-214 308  Example 1  41  (single bond) OH      Me Me Cl Cl S MeS 119-121 334  Example 1  42  (single bond) OH Me Me Cl      Cl S p-MeOPhNH 169-170 409  Example 1  43  (single bond) OH Me Me Cl Cl      S PhNH 142-143 379  Example 1  44  (single bond) OH Me Me H NO.sub.2 S      MeNH 148-149 294  Example 1  45  (single bond) OH Me Et H CN S MeNH      136-139 288  Example 1  46  (single bond) OH Me Me H SO.sub.2 Ph S MeNH      182-183 389  Example 1  47  (single bond) OH Me Me H CN S EtNH 134-136      288  Example 1  48  (single bond) OH Me Me H CN O EtO 124-125 273      Example 1  49  (single bond) OH Me Me H OMe S MeNH 123-124 279  Example      1  50  (single bond) OH Me Me H CN S Me.sub.2 CHCH.sub.2 NH 124-126 316      Example 1  51  (single bond) OH Me Me H CN S p-MeOPhNH 173-175 366      Example 1  52  (single bond) OH Me Me H CN O EtNH 126-127 272  Example 1       53  (single bond) OH Me Me H CN O MeNH 200-201 258  Example 1  54      (single bond) OH Me Me H NO.sub.2 O MeNH 151-152 278  Example 1  55 Me O M      e Me H CN S MeNH 157.5-159 288  Example 1  56 H O Me Me H CN S Me.sub.2      N 127-129 288  Example 1  57  (single bond) OH Et H H NO.sub.2 S MeNH      172-173 294  Example 1  58  (single bond) OH t-Bu H H NO.sub.2 S MeNH      174-176 322  Example 1  59  (single bond) OH Me n-Pr H NO.sub.2 S MeNH      141-142 322  Example 1  60  (single bond) OH (CH.sub.2).sub.3 H NO.sub.2 S       MeNH 177-178 306  Example 1  61  (single bond) OH (CH.sub.2).sub.5 H      NO.sub.2 S MeNH 205-208 334  Example 1  62  (single bond) OH Me Me H CN      O Me.sub.2 CHNH 122-124 286  Example 1  63  (single bond) OH Me Me Cl Cl      O MeNH 125-126 301  Example 1  64  (single bond) OH Me Me NO.sub.2      NHCOMe O MeNH 189-193 335  Example 1  65  (single bond) OH Me Me NON O      MeNH 150-152 275  Example 1  66   (single bond) OH Me Me H Et S MeNH      125-127 277  Example 1  67  (single bond) OH Me Me H CF.sub.3 S MeNH      144-145 317  Example 1  68  (single bond) OH Me Me NO.sub.2 H O MeNH      156-158 294  Example 1  69  (single bond) OH Me Me H Br O MeNH 132-134      311  Example 1  70 Ph O Me Me H CN S MeNH 236.5-238 350  Example 1  71*      H OH H Me Me Cl Cl S MeNH 156-157 319  Example 2  72* H OH H Me Me Cl Cl      S MeNH 183-185 319  Example 2  73 H OH H Me Me Cl CN S MeNH 181-183 310      Example 2 (cis form)   74 H OH H Me Me Cl CN S MeNH 210-212 310  Example      2 (trans form)   75 H OH H Me Me H NO.sub.2 S MeNH 203-207 296  Example      2  76 H OH H Me Me H SO.sub.2 Ph S MeNH 183-184 391  Example 2  77 Me OH      H Me Me H CN S MeNH 248-250 290  Example 2  78 H OH H Me Me H CN O MeNH      188-189 260  Example 2 (cis form)   79 H OH H Me Me H CN O MeNH 210-211      260  Example 2 (trans form)   80 H OH H Me Me H NO.sub.2 O MeNH 209-211      280  Example 2  81 H OH H Me Me H CN O Me.sub.2 CHNH 188-189 288      Example 2  82  (single bond) H Me Me Cl Cl S MeNH 155-156 301  Example 3       83  (single bond) H Me Me Cl CN S MeNH 144-145 292  Example 3  84      (single bond) H Me Me H SO.sub.2 Ph S MeNH  93-95 373  Example 3  85      (single bond) H Me Me H CN O MeNH 198-199 242  Example 3  86  (single      bond) H Me Me H NO.sub.2 O MeNH 165-166 262  Example 3  87  (single      bond) H Me Me H CN S p-ClPhNH 160-162 354  Example 3  88  (single bond)      H Me Me H COOMe S MeNH 207-208 291  Example 3  89  (single bond) H Me Me      H SO.sub.2 Me S MeMH 138-139 311  Example 3  90  (single bond) H Me Et H      NO.sub.2 S MeNH 139-140 292  Example 3  91       (single bond) H (CH.sub.2).sub.5  H NO.sub.2 S MeNH 212-215 318      Example 3  92  (single bond) H Me Me H Et S MeNH 110-111 261  Example 3  9      3  (single bond) H (CH.sub.2).sub.6  H NO.sub.2 S MeNH 158-159 332      Example 3  94  (single bond) H Me Me Cl Cl O PhNH 206-207 347  Example 7       95  (single bond) H Me Me Cl Cl S p-MeOPhNH 133-134 393  Example 7  96  (      single bond) H Me Me Cl Cl S PhNH 133-134 363  Example 7  97   (single      bond) H Me Me H CN O EtNH 173-174 256  Example 7  98  (single bond) H Me      Me H OMe S MeNH 107-108 263  Example 7  99  (single bond) H Me Me H CN S      Me.sub.2 CHCH.sub.2 NH 102-106 300  Example 7 100  (single bond) H Me Me      H CN S p-MeOPhNH  -- 350 2224 Example 7  (CN) 101  (single bond) H Me Me      H CN S PhNH 153-156 320  Example 7 102  (single bond) H Me Me H CN O      PhNH 242-243 304  Example 7 103  (single bond) H Me Me H Cl S MeNH      138-140 267  Example 9 104  (single bond) H Me Me H CF.sub.3 S MeNH      150-151 301  Example 9 105  (single bond) H Me Me H OCF.sub.3 S MeNH      124-125 317  Example 9 106  (single bond) H Me Me H SO.sub.2 Me S      Me.sub.2 N 151-152 325  Example 9 107  (single bond) H Me Me H CN S      Me.sub.2 N 172-173 272  Example 9 108  (single bond) H Me Me H CN S      Me.sub.2 CHNH 172-174 286  Example 9 109  (single bond) H Me Me H CN S      m-ClPhNH 156-158 354  Example 9 110  (single bond) H Me Me H CN S      o-ClPhNH 146.5-148 354  Example 9 111  (single bond) H (CH.sub.2).sub.4  H       CN S MeNH 196-197 284  Example 9 112  (single bond) H Me Me H NO.sub.2      S NH.sub.2 151-152 264  Example 9 113  (single bond) H Me Me H NO.sub.2      S EtNH 149.5-151 292  Example 9 114  (single bond) H Me Me H NO.sub.2 S      Et.sub.2 N 130-132 320  Example 9 115  (single bond) H Me Me H NO.sub.2      S n-PrNH 101-102 306  Example 9 116  (single bond) H Me Me H NO.sub.2 S      Me.sub.2 CHNH 145-147 306  Example 9 117  (single bond) H Me Me H      NO.sub.2 S n-BuNH 119-121 320  Example 9 118  (single bond) H Me Me H      NO.sub.2 S HOCH.sub.2 CH.sub.2 NH 154-156 308  Example 9 119  (single      bond) H Me Me H NO.sub.2 S MeNCHMe.sub.2 143.5-145 320  Example 9 120      (single bond) H Me Me H NO.sub.2 S PhNH 152.5-155 340  Example 9   121      (single bond) H Me Me H NO.sub.2 S       ##STR52##       153-154 304  Example 9   122  (single bond) H Me Me H NO.sub.2 S       ##STR53##       180-181 318  Example 9   123  (single bond) H Me Me H NO.sub.2 S       ##STR54##       171-173 332  Example 9   124  (single bond) H Me Me H NO.sub.2 S       ##STR55##       186-187 433  Example 9   125  (single bond) H t-Bu H H NO.sub.2 S MeNH      156-157 306  Example 9 126  (single bond) H Et Et H NO.sub.2 S MeNH      127-128 306  Example 9 127  (single bond) H (CH.sub.2).sub.3  H NO.sub.2 S       MeNH 165-166 290  Example 9 128  (single bond) H (CH.sub.2).sub.4 H      NO.sub.2 S MeNH 191-192 304  Example 9 129  (single bond) H Me Me NON S      NH.sub.2 160-162 261  Example 9 130  (single bond) H Me Me NON S MeNH      215-216 275  Example 9  131  (single bond) H Me Me NON S Me.sub.2 N      160-161 289  Example 9 132  (single bond) H Me Me H NO.sub.2 S MeMEt      100-103 306  Example 9 133       (single bond) H Me Me H NO.sub.2 S MeNCH.sub.2 Ph 162-163 368  Example      9 134  (single bond) H Me Me H Br S MeNH 136-138 311  Example 9   135      (single bond) H Me Me H NO.sub.2 S       ##STR56##       158-159 347  Example 9   136  (single bond) H Me Me H NO.sub.2 S       ##STR57##       184-186 334  Example 9   137  (single bond) H Me Me H NO.sub.2 S      cyc-PrNH 121-123 304  Example 9 138  (single bond) H Me Me H NO.sub.2 S      t-BuOCOCH.sub.2 NH 142-143 378  Example 9 139  (single bond) H Me Me H      NO.sub.2 S Me.sub.2 N 139-141 292  Example 9 140  (single bond) H Me Me      Cl CN NCN Me.sub.2 N 193-194 314  Example 10(3) 141  (single bond) H Me      Me H CN NCN Me.sub.2 N 219-221 280  Example 10(3) 142  (single bond) H      Me Me H NO.sub.2 O NCNH 178-180 273  Example 13 143  (single bond) H Me      Me H NO.sub.2 O MeONH 161-163 278  Example 13 144  (single bond) H Me Me      H NO.sub.2 O MeNOH 162-163 278  Example 13 145  (single bond) H Me Me H      NO.sub.2 O HOCH.sub.2 CH.sub.2 NH 157.5-159 292  Example 13 146  (single      bond) H Me Me H NO.sub.2 O n-PrNH 143-144 290  Example 13 147  (single      bond) H Me Me H NO.sub.2 O n-BuNH  92-93 304  Example 13 148  (single      bond) H Me Me H NO.sub.2 O cyc-PrNH 143-146 288  Example 13 149  (single      bond) H Me Me H NO.sub.2 O t-BuOCOCH.sub.2 NH 180-182 362  Example 13      150  (single bond) H Me Me H NO.sub.2 O n-Pr.sub.2 N  73-74 332  Example      13 151  (single bond) H Me Me H NO.sub.2 O i-Pr.sub.2 N 117-119 278      Example 13 152  (single bond) H Me Me H NO.sub.2 O n-Bu.sub.2 N oily 360      1630 Example 13  (CO) 153  (single bond) H Me Me H NO.sub.2 O Ph.sub.2 N      163-164 400  Example 13  154  (single bond) H Me Me H NO.sub.2 O       ##STR58##       149-150 288  Example 13  155  (single bond) H Me Me H NO.sub.2 O       ##STR59##       195-196 302  Example 13  156  (single bond) H Me Me H NO.sub.2 O       ##STR60##       130-135 417  Example 13  157  (single bond) H Me Me H NO.sub.2 O       ##STR61##       189-191 316  Example 13  158  (single bond) H Me Me H NO.sub.2 O       ##STR62##       189-192 318  Example 13  159  (single bond) H Me Me H NO.sub.2 O       ##STR63##       235-237 331  Example 13   160  (single bond) H Me Me H NO.sub.2 O       ##STR64##       177-178 330  Example 13   161  (single bond) H Me Me NON O MeNH 201-202 2      59  Example 13 162  (single bond) H Me Me NON O Me.sub.2 N 177-178 273      Example 13 163  (single bond) H Me Me H NO.sub.2 NCN MeNCH.sub.2      CH.sub.2 OH 158-159 330  Example 14 164  (single bond) H Me Me H      NO.sub.2 NCN HNCH.sub.2 CH.sub.2 OH 174.5-175.5 316  Example 14 165      (single bond) H Me Me H Br O MeNH 157-160 295  Example 10(3) 166      (single bond) H Me Me Cl Cl O MeNH 172-173 285  Example 10(3) 167      (single bond) H Me Me H CN O Me.sub.2 CHNH 135-137 270  Example 10(3)      168  (single bond) H Me Me H CN O m-ClPhNH 240.5-241.5 338  Example      10(3) 169  (single bond) H Me Me H CN O o-ClPhNH 231-232.5 338  Example      10(3) 170  (single bond) H Me Me H NO.sub.2 O NH.sub.2 144-145 248      Example 10(3) 171  (single bond) H Me Me H NO.sub.2 O Me.sub.2 CHNH      119-120 290  Example 10(3) 172  (single bond) H Me Me H H O MeNH 161-163      217  Example 15 173  (single bond) H Me Me H Cl O MeNH 166-167 251      Example 15 174  (single bond) H Me Me H OCF.sub.3 O MeNH 159-160 301      Example 15 175  (single bond) H Me Me H SO.sub.2 Me O MeNH  76-78 295      Example 15 176  (single bond) H Me Me H COOMe O MeNH 110-111 275      Example 15 177  (single bond) H (CH.sub.2).sub.4  H CN O MeNH 196-197      268  Example 15 178  (single bond) H Me Me H NO.sub.2 O EtNH 153-155 276       Example 15 179  (single bond) H Et H H NO.sub.2 O MeNH 157-159 262      Example 15 180  (single bond) H t-Bu H H NO.sub.2 O MeNH 156-157 290      Example 15 181  (single bond) H Me Et H NO.sub.2 O MeNH 144-145 276      Example 15 182  (single bond) H Me n-Pr H NO.sub.2 O MeNH 127-129 290      Example 15 183  (single bond) H Et Et H NO.sub.2 O MeNH 143-144 290      Example 15 184  (single bond) H (CH.sub.2).sub.3  H NO.sub.2 O MeNH      228-229 274  Example 15 185  (single bond) H (CH.sub.2).sub.4  H      NO.sub.2 O MeNH 208-209 288  Example 15 186       (single bond) H (CH.sub.2).sub.5  H NO.sub.2 O MeNH 172-173 302      Example 15 187  (single bond) H (CH.sub.2).sub.6  H NO.sub.2 O MeNH      171-172 316  Example 15 188  (single bond) H Me Me Cl CN  O MeNH 158-159 2      76  Example 16 189  (single bond) H Me Me H SO.sub.2 Ph O MeNH 158-159      357  Example 16 190  (single bond) H Me Me H NO.sub.2 O PhNH 211-212 324       Example 16 191  (single bond) H Me Me H CN O Me.sub.2 N  95-96 256      Example 17 192  (single bond) H Me Me H SO.sub.2 Me O Me.sub.2 N 159-161      309  Example 17 193  (single bond) H Me Me H NO.sub.2 O Et.sub.2 N      75-76 304  Example 17 194       (single bond) H Me Me H NO.sub.2 O MeNCHMe.sub.2  141-142 304  Example      17 195  (single bond) H Me Me H NO.sub.2 O MeNOMe  96-98 292  Example 17      196  (single bond) H Me Me H NO.sub.2 O EtNOMe  63-65 306  Example 17      197  (single bond) H Me Me H NO.sub.2 O MeNCH.sub.2 Ph 114-116 352      Example 17 198  (single bond) H Me Me H NO.sub.2 O MeNCN 123-124 287      Example 17 199  (single bond) H Me Me H NO.sub.2 NCN NCNH 281-284 297      Example 21 200  (single bond) H Me Me H NO.sub.2 NCN MeNOMe 145-146 316      Example 21 201  (single bond) H Me Me H NO.sub.2 NCN CF.sub.3 CH.sub.2      NH 204-205 354  Example 21 202  (single bond) H Me Me H NO.sub.2 NCN      t-BuNH 235-237 328  Example 21 203  (single bond) H Me Me H NO.sub.2 NCN      i-BuNH 200-201 328  Example 21 204  (single bond) H Me Me H NO.sub.2 NCN      t-BuCH.sub.2 NH 187-188 342  Example 21 205  (single bond) H Me Me H      NO.sub.2 NCN cyc-PenNH 203-205 340  Example 21 206  (single bond) H Me      Me H NO.sub.2 NCN t-BuOCOCH.sub.2 NH 181-182 386  Example 21 207      (single bond) H Me Me H NO.sub.2 NCN HOCH.sub.2 CH(Me)NH 163-164 330      Example 21 208  (single bond) H Me Me H NO.sub.2 NCN PhCH.sub.2 NH      193-195 362  Example 21 209  (single bond) H Me Me H NO.sub.2 NCN      n-Pr.sub.2 N 162-164 356  Example 21 210  (single bond) H Me Me H      NO.sub.2 NCN n-Bu.sub.2 N 141-142 384  Example 21  211  (single bond) H      Me Me H NO.sub.2 NCN       ##STR65##       176-178 355  Example 21   212 H H H Me Me H CN S MeNH 174-175 260      Example 22 213 H H H Me Me H NO.sub.2 S MeNH 161-162 280  Example 22 214       (single bond) OH Me Me H CN O NHOMe 160.5-163 274  Example 29 215       (single bond) OH Me Me H CN O NH.sub.2 208-210 244  Example 29 216      (single bond) H Me Me H Cl NCN Me.sub.2 N 167-168 289  Example 36 217      (single bond) H Me Me H Br NCN Me.sub.2 N 164-165 333  Example 36 218      (single bond) H Me Me H CF.sub.3 NCN Me.sub.2 N 132-133 323  Example 36      219  (single bond) H Me Me H SO.sub.2 Me NCN Me.sub.2 N 246-247 333      Example 36 220  (single bond) H Me Me H SO.sub.2 Ph NCN Me.sub.2 N      200-201 395  Example 36 221  (single bond) H Me Me NON NCN Me.sub.2 N      186-187 297  Example 36 222  (single bond) H Me Me H NO.sub.2 NCN      Et.sub.2 N 159-161 328  Example 36 223  (single bond) H Me Me H NO.sub.      2 NCN MeNCHMe.sub.2  165-166 328  Example 36 224  (single bond) H Me Me      H NO.sub.2 NCN MeNEt 151-152 314  Example 36 225  (single bond) H Me Me      H NO.sub.2 NCN MeNCH.sub.2 Ph 183-186 376  Example 36 226  (single bond)      H Me Me H NO.sub.2 NCN MeN(CH.sub.2).sub.2 OSiMe.sub.2 (t-Bu) 157-158      444  Example 36 227  (single bond) H Me Me H NO.sub.2 NCN MeNCH.sub.2      COOEt 149-150 372  Example 36  228  (single bond) H Me Me H NO.sub.2 NCN       ##STR66##       240-243 312  Example 36  229  (single bond) H Me Me H NO.sub.2 NCN       ##STR67##       213-214 326  Example 36  230  (single bond) H Me Me H NO.sub.2 NCN       ##STR68##       183-184 441  Example 36  231  (single bond) H Me Me H NO.sub.2 NCN       ##STR69##       181-182 456  Example 36  232  (single bond) H Me Me H NO.sub.2 NCN       ##STR70##       182-183 340  Example 36  233  (single bond) H Me Me H NO.sub.2 NCN       ##STR71##       183-184 342  Example 36  234  (single bond) H Et H H NO.sub.2 NCN      Me.sub.2 N 159-161 300  Example 36 235  (single bond) H t-Bu H H      NO.sub.2 NCN Me.sub.2 N 220-221 328  Example 36 236  (single bond) H Me      Et H NO.sub.2 NCN Me.sub.2 N 160-161 314  Example 36 237  (single bond)      H Me n-Pr H NO.sub.2 NCN Me.sub.2 N  97-100 328  Example 36 238  (single      bond) H Et Et H NO.sub.2 NCN Me.sub.2 N 130-131 328  Example 36 239       (single bond) H (CH.sub.2).sub.4  H NO.sub.2 NCN Me.sub.2 N 218-219 326       Example 36 240  (single bond) H (CH.sub.2).sub.5 H NO.sub.2 NCN      Me.sub.2 N 203-204 340  Example 36 241  (single bond) H Me Me H Br NCN      MeNH 215-216 319  Example 37 242  (single bond) H Me Me Cl CN NCN MeNH      275-276 300  Example 37 243  (single bond) H Me Me H SO.sub.2 Me NCN      MeNH 234-235 319  Example 37 244  (single bond) H Me Me H SO.sub.2 Ph      NCN MeNH 118-120 381  Example 37 245  (single bond) H Me Me H NO.sub.2      NCN EtNH 198-200 300  Example 37 246  (single bond) H Me Me H NO.sub.2      NCN Me.sub.2 CHNH 237-239 314  Example 37 247  (single bond) H Me Et H      NO.sub.2 NCN MeNH 213-214 300  Example 37 248  (single bond) H Me Me H      CN NCN MeNH 261-263 266  Example 37 249  (single bond) H t-Bu H H      NO.sub.2 NCN MeNH 221-223 314  Example 37 250  (single bond) OH Me Me H      SO.sub.2 Me S MeNH 103-104 327  Example 1 251  (single bond) OH Me Me H      Cl S MeNH 137-138 283  Example 1 252  (single bond) OH Me Me H OCF.sub.3      S MeNH  92-93 333  Example 1 253  (single bond) OH Me Et H NO.sub.2 S      MeNH 189-190 308  Example 1 254  (single bond) OH Et Et H NO.sub.2 S      MeNH 217-218 322  Example 1 255  (single bond) OH (CH.sub.2).sub.4  H      NO.sub.2 S MeNH 206-207 320  Example 1 256       (single bond) OH (CH.sub.2).sub.6 H NO.sub.2 S MeNH 190-193 348      Example 1 257   (single bond) OH (CH.sub.2).sub.4 H CN S MeNH 186-189      300  Example 1 258  (single bond) H Me n-Pr H NO.sub.2 S MeNH oily 306      1512 Example 3            (NO.sub.2)            1340            (NO.sub.2      ) 259  (single bond) H Me Me H NO.sub.2 S n-Pr.sub.2 N 111-113 348      Example 9 260  (single bond) H Me Me H OCF.sub.3 NCN Me.sub.2 N 123-124      339  Example 36 261  (single bond) H Me Me Cl Cl NCN Me.sub.2 N 149-151      324  Example 36 262  (single bond) H (CH.sub.2).sub.4  H CN NCN Me.sub.2      N 256-258 306  Example 36 263  (single bond) H (CH.sub.2).sub. 6 H      NO.sub.2 NCN Me.sub.2 N 196-197 354  Example 36 264  (single bond) H Me      Me H NO.sub.2 CHNO.sub.2 Me.sub.2 N 217-219 319  Example 36 265  (single      bond) H Me Me H OCF.sub.3 NCN MeNH 151-152 325  Example 37 266  (single      bond) H Me Me H Cl NCN MeNH 203-204 275  Example 37 267  (single bond) H      Me Me Cl Cl NCN MeNH 205-208 310  Example 37 268  (single bond) H Me      n-Pr H NO.sub.2 NCN MeNH 152-154 314  Example 37 269  (single bond) H Et      Et H NO.sub.2 NCN MeNH 192-193 314  Example 37 270  (single bond) H      (CH.sub.2).sub.4  H NO.sub.2 NCN MeNH 227-229 312  Example 37 271      (single bond) H (CH.sub.2).sub.6 H NO.sub.2 NCN MeNH 229-231 340      Example 37 272  (single bond) H (CH.sub.2).sub.4 H CN NCN MeNH 255-257      292  Example 37 273  (single bond) H Me Me NON NCN MeNH 250-252 283      Example 37 274  (single bond) H Me Me H NO.sub.2 NCN NH.sub.2 CONHNH      183-187 330  Example 21  275  (single bond) H Me Me H NO.sub.2 O       ##STR72##       292-295 332  Example 13  276  (single bond) H Me Me H NO.sub.2 O 2-PyNH       97-101 325  Example 13 277  (single bond) H Me Me H NO.sub.2 O 3-PyNH      186-188 325  Example 13  278  (single bond) H Me Me H NO.sub.2 O       ##STR73##       207-210 331  Example 13  279  (single bond) H Me Me H NO.sub.2 O      BrCH.sub.2 CH.sub.2 NH 150-152 354  Example 13  280  (single bond) H Me      Me H NO.sub.2 O       ##STR74##       233-236 316  Example 13  281  (single bond) H Me Me H NO.sub.2 O       ##STR75##       140-142 274  Example 13  282  (single bond) H Me Me H NO.sub.2 O      cyc-HexNH 141-142 330  Example 13 283  (single bond) H Me Me H NO.sub.2      O CHCCH.sub.2 NH 188-190 286  Example 13 284  (single bond) H Me Me H      NO.sub.2 O NH.sub.2 CONHNH 206-208 306  Example 13 285  (single bond) H      Me Me H NO.sub.2 O cyc-PenNH 168-170 316  Example 13 286  (single bond)      H Me Me H NO.sub.2 O i-BuONH 161-163 320  Example 13 287  (single bond)      H Me Me H NO.sub.2 O MeOCH.sub.2 CH.sub.2 NH 112-114 306  Example 13 288       (single bond) H Me Me H NO.sub.2 O NCCH.sub.2 CH.sub.2 NH 145-146 301      Example 13 289  (single bond) H Me Me H NO.sub.2 O cyc-BuNH 157-158 302      Example 13 290  (single bond) H Me Me H NO.sub.2 O NCCH.sub.2 NH 196-197      287  Example 13 291  (single bond) H Me Me H NO.sub.2 O CH.sub.2      CHCH.sub.2 NH 153-155 288  Example 13 292  (single bond) H Me Me H      NO.sub.2 O NMe.sub.2 CH.sub.2 CH.sub.2 NH 113-116 319  Example 13 293      (single bond) H Me Me H NO.sub.2 O PhCH.sub.2 ONH 134-135 354  Example      13 294  (single bond) H Me Me H NO.sub.2 O 4-PyNH 242-245 325  Example      13 295  (single bond) H Me Me H NO.sub. 2 O MeNHCH.sub.2 CH.sub.2 NH      122-125 305  Example 13 296  (single bond) H Me Me H NO.sub.2 O Me.sub.2      NNH 140-142 291  Example 13 297  (single bond) H Me Me H NO.sub.2 O      cyc-PrCH.sub.2 NH 161-163 302  Example 13 298  (single bond) H Me Me H      NO.sub.2 O NH.sub.2 CH.sub.2 CH.sub.2 NH 143-145 291  Example 13 299      (single bond) H Me Me H NO.sub.2 O FCH.sub.2 CH.sub.2 NH 167-169 294      Example 13 300  (single bond) H Me Me H NO.sub.2 O MeSCH.sub.2 CH.sub.2      NH 117-119 322  Example 13 301  (single bond) H Me Me H NO.sub.2 O      MeCOCH.sub.2 NH 170-171 304  Example 17 302  (single bond) H Me Me H      NO.sub.2 O EtONH 139-141 292  Example 13 303  (single bond) H Me Me H      NO.sub.2 O n-PrONH 158-159 306  Example 13 304  (single bond) H Me Me H      NO.sub.2 O n-BuONH 150-151 320  Example 13  305  (single bond) H Me Me H      NO.sub.2 O       ##STR76##       255-257 359  Example 13  306  (single bond) H Me Me H NO.sub.2 O       ##STR77##       175-178 355  Example 13  307  (single bond) H Me Me H NO.sub.2 O       ##STR78##        96-100 326  Example 13  308  (single bond) H Me Me H NO.sub.2 O       ##STR79##       268-272 342  Example 13  309  (single bond) OH (CH.sub.2).sub.5  H      NO.sub.2 S CH.sub.2 CHCH.sub.2 NH 132-136 360  Example 1 310  (single      bond) H (CH.sub.2 ).sub.5  H NO.sub.2 O CH.sub.2 CHCH.sub.2 NH 121-122      328  Example 15              311  (single bond) H Me Me H NO.sub.2 O       ##STR80##       118-123 299  Example 13  312  (single bond) H Me Me H NO.sub.2 O      NH.sub.2 NMe 192-195 277  Example 13 313  (single bond) H Me Me H      NO.sub.2 O CHCCH.sub.2 ONH 138-140 302  Example 13 314  (single bond) H      Me Me H NO.sub.2 O NCCH.sub.2 CH.sub.2 CH.sub.2 NH  -- 315 2252 Example      17 315  (single bond) H Me Me H NO.sub.2 O NCCH.sub.2 CH.sub.2 CH.sub.2      CH.sub.2 NH      *The configurations of 3 and 4positions of compounds 71 and 72 were not      determined

Excellent activities of the compounds of the present invention on the K⁺ channel will now be demonstrated below by way of Test Examples.

TEST EXAMPLE 1 Test with Excised Aorta of Rat

The thoracic aorta was excised from a male Sprague Dawley rat (450 to 600 g) and cut into 2 mm wide ring preparations. Each preparation was suspended in 10 ml of an organ bath containing a Krebs-Henseleit solution (NaCl:119; KCl:4.8; CaCl₂ ·2H₂ O: 2.53; KH₂ PO₄ :1.2; MgSO₄ ·7H₂ O: 1.2; NaHCO₃ : 24.8; glucose: 10 (mM); 37° C.) under a tension of 2 g, and a mixed gas of 95% O₂ and 5% CO₂ was bubbled therethrough. Isometric contractions of the preparation were recorded by means of an FD pick-up. After equilibrium was reached in 1 to 1.5 hours, 30 mM KCl was added to cause a tissue contraction. The activity of a test compound to relax a lasting contraction following the KCl addition was evaluated by obtaining a 50% inhibitory concentration (IC₅₀).

The compounds of the present invention obtained in the foregoing Examples and, for comparison, Cromakalim were used as test compounds. The results obtained are shown in Table 3 below.

TEST EXAMPLE 2

Test with Guinea Pig Tracheal Muscle

The trachea was excised from a male Hartley guinea pig (450 to 550 g) to make chain preparations. The preparation was suspended in a bath containing the same Krebs-Henseleit solution as used in Test Example 1 (37° C.) through which a mixed gas of 95% O₂ and 5% CO₂ was bubbled. Isometric contractions of the preparation were recorded under a tension of 1 g. The relaxing activity of 1 mM aminophylline on spontaneous tension being taken as 100%, a concentration of a test compound exhibiting 50% relaxing activity (IC₅₀) was obtained.

The same test compounds as used in Test Example 1 were used. The results obtained are shown in Table 3.

                  TABLE 3                                                          ______________________________________                                                                  Guinea Pig                                                         Rat Aorta   Tracheal Muscle                                       Compound     IC.sub.50   IC.sub.50                                             No.          (M)         (M)                                                   ______________________________________                                          3           3.3 × 10.sup.-8                                                                      2.0 × 10.sup.-7                                  8           1.4 × 10.sup.-9                                                                      6.3 × 10.sup.-9                                  10          1.1 × 10.sup.-8                                                                      3.3 × 10.sup.-8                                  11          >3.0 × 10.sup.-5                                                                     5.4 × 10.sup.-8                                  12          1.1 × 10.sup.-8                                                                      2.3 × 10.sup.-8                                  22          1.4 × 10.sup.-8                                                                      3.6 × 10.sup.-8                                  90          .sup. 1.8 × 10.sup.-10                                                               2.9 × 10.sup.-9                                  91          .sup. 1.4 × 10.sup.-10                                                               3.8 × 10.sup.-8                                 104          2.6 × 10.sup.-9                                                                      3.7 × 10.sup.-8                                 113          3.7 × 10.sup.-9                                                                      1.1 × 10.sup.-8                                 115          3.0 × 10.sup.-9                                                                      4.1 × 10.sup.-8                                 128          .sup. 3.7 × 10.sup.-11                                                               5.0 ×  10.sup.-8                                134          9.3 × 10.sup.-9                                                                      7.5 × 10.sup.-8                                 137          3.7 × 10.sup.-9                                                                      2.2 × 10.sup.-8                                 146          5.7 × 10.sup.-9                                                                      5.6 × 10.sup.-8                                 181          2.1 × 10.sup.-9                                                                      1.6 × 10.sup.-8                                 186          .sup. 4.2 × 10.sup.-11                                                               1.1 × 10.sup.-8                                 193          6.0 × 10.sup.-6                                                                      5.7 × 10.sup.-8                                 Cromakalim   1.8 × 10.sup.-7                                                                      7.9 × 10.sup.-7                                 ______________________________________                                    

TEST EXAMPLE 3 Study on Antiasthmatic Activity

A mid-line incision was made in the neck of a male Hartley guinea pig (600 to 800 g, CRJ) under anesthesia with pentobarbitar (40 mg/kg, i.p.). The trachea, the left carotid vein, and the left carotid artery were exposed, and a cannula was inserted into each of them. The inner pressure of the respiratory tract was measured while applying artificial respiration through the tracheal cannula. The blood pressure was measured through the arterial cannula, and the heart rate was determined from the pulse. Pentobarbital for anesthesia maintenance was continuously administered through the venous cannula. A mid-line incision was made on the abdomen to expose the duodenum, and a cannula for intraduodenal administration was inserted thereinto. After the postoperative convalescence of 30 to 60 minutes, histamine (5 to 10 μg/kg) was intravenously administered every 10 minutes. After it was confirmed that a respiratory tract inner pressure rise reaction was stably obtained, a test compound in the form of a 0.3% CMC suspension was intraduodenally administered. The histamine dose was so selected that the respiratory tract inner pressure might rise to 20 to 40 cmH₂ O after every lntravenous administration. After administration of the test compound, intravenous administration of histamine at 10 minutes intervals was continued. The histamine-induced increase in respiratory tract inner pressure after the administration of the test compound was compared with that before the administration.

The activity of the test compound, expressed in terms of dose level required for 50% inhibition of the histamine-induced increase in respiratory tract inner pressure (ED₅₀, mg/kg), is shown in Table 4 below.

                  TABLE 4                                                          ______________________________________                                         Compound No.  ED.sub.50 (mg/kg)                                                ______________________________________                                          8            0.1-0.3                                                          10            <0.1                                                             11             0.1                                                             12            0.1-0.3                                                          22            <0.3                                                             181           0.1-0.3                                                          193           <0.3                                                             Cromakalim    1.0-3.0                                                          ______________________________________                                    

UTILITY OF THE INVENTION IN INDUSTRY

The novel compounds of the present invention have excellent K⁺ channel activating activity and are therefore expected to make great contribution to the art, such as medical compositions utilizing K⁺ channel activation (e.g., anti-asthmatics). 

What is claimed is:
 1. A benzopyran derivative represented by the formula: ##STR81## wherein X is an oxygen atom or a sulfur atom, Y represents --NR₈ R₉ wherein R₈ and R₉ represent a substituted lower alkyl with the proviso that the substituent is not lower alkyl or a hydrogen atom, provided that at least one of R₈ and R₉ is a said substituted lower alkyl,R₁ represents a hydrogen atom, a lower alkyl group or an aryl group, or it is directly bonded to R₂ to form a single bond, R₂ and R₃, which may be the same or different, each represents a hydrogen atom or a hydroxyl group, or they are taken together to form =O, or R₂ is directly bonded to R₁ to form a single bond, R₄ and R₅, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, or they are taken together to form a polymethylene group, and R₆ and R₇ represent a nitro group or a hydrogen atom, provided that at least one of R₆ and R₇ is a nitro group.
 2. A benzopyran derivative according to claim 1 wherein X is oxygen.
 3. A compound according to claim 1 wherein R₁ and R₂ form a single bond.
 4. A compound according to claim 1 wherein R₃ is hydrogen.
 5. A compound according to claim 1 wherein at least one R₄ and R₅ is lower alkyl.
 6. A compound according to claim 5 wherein both R₄ and R₅ are methyl.
 7. A compound according to claim 1 wherein one of R₈ and R₉ is hydrogen.
 8. A compound according to claim 1 wherein one of R₈ and R₉ is cyano substituted lower alkyl.
 9. A compound according to claim 1 wherein R₈ or R₉ is --CH₂ CH₂ CN.
 10. A compound according to claim 1 wherein X is oxygen; R₁ +R₂ form a single bond; R₄ is hydrogen; R₃ and R₅ are both methyl; one of R₆ and R₇ is hydrogen and the other of R₆ and R₇ is nitro; and one of R₈ and R₉ is hydrogen and the other of R₈ and R₉ is --CH₂ CH₂ CN. 